PROJECT SUMMARY/ABSTRACT The balance between hepatocyte life and death is regulated through multiple signaling pathways. Activation of the mitogen-activated protein kinase (MAPK) pathway represents an important and fundamental mechanism through which hepatocyte function and longevity is achieved. Although propagation of the stress-responsive MAPKs is critical for the promotion of both signals that confer hepatocyte life and death much less is understood about the signals that inactivate the MAPKs in the liver and how these signals participate in the progression of liver disease. The broad goal of this project is to define the role of the MAP kinase phosphatase-1 (MKP-1) in the management of liver injury. Liver injury is often one of the early precipitating events in the progression towards liver disaease that is often facilitated by chronic inflammation. We have found that whole body MKP-1-deficient mice exhibit resistance to the development of non-alcoholic steatohepatitis (NASH) and in response to injury are impaired in their ability to regenerate liver. We will test the hypothesis that hepatic MKP-1 serves as an essential regulator of stress-responsive MAPK signaling in the control of liver injury. In aim 1, we will use liver-specific MKP-1 knock-out mice to determine the contribution of MKP-1 in the liver and macrophage in the progression of NASH. Aim 2 will focus on the observation that hepatic MKP-1 is required for liver regeneration. We will will elucidate the mechanisms through which MKP-1 regulates liver regeneration by examining how it serves to control the expression of the hepatokine, interleukin 6. In aim 3, phosphoproteomic approaches will be employed to identify MKP-1-regulated MAPK substrates involved in liver stress and repair. Hepatic MKP-1-regulated MAPK substrates will be characterized and tested for their roles in liver stress-responsive signaling. These studies will be integrated with the analysis of MKP-1 and its identified regulatory MAPK substrates in various human settings of liver disease. The succesful implementation of these studies will provide new insight in to the mechanisms the liver invokes in response to injury and as such may reveal new therapeutic avenues for the treatment of liver disease.